This invention relates to a novel process for the production of mono-substituted terminal diesters of malonic acid. These diesters have utility as starting materials and intermediates for the synthesis of pharmacologically active compounds such as the barbituates and related hypnotics, sedatives, tranquilizers and anesthetics.
In 1903 Emil Fischer and J. von Mering synthesized a number of derivatives of barbituric acid by condensing urea with diethyl malonate (commonly called malonic ester) under the influence of sodium ethoxide as a condensing agent. Some of these derivatives were found by these scientists to be valuable as soporifics. The preparation of the lead compound of these 5,5'-disubstituted barbiturates, namely 5,5'-diethylbarbituric acid (Veronal.RTM., barbital), as described in German Patent No. 146,496 (1903), can be illustrated as follows: ##STR1##
Several hundreds of these barbiturate derivatives having various hypnotic, sedative, tranquilizing and anesthetic activities have since been synthesized. See Blicke and Cox, Medicinal Chemistry, Vol. IV, page 1, John Wiley & Sons, New York, 1963. These compounds are especially useful as the sodium salts for absorption from the gastrointestinal tract or for administration through the parenteral route.
The derivatives of barbituric acid now constitute one of the more venerable families of medicinal agents. The aforesaid lead member of the series, barbital, has been in continuous use since its discovery in 1903. The final step in the synthesis of many of the barbiturates consists in either condensation of an organo-substituted malonic or cyanoacetic ester with urea by means of sodium ethoxide or analogous condensation of such an ester with guanidine followed by hydrolysis of the imine thus produced. The chemistry of this class of medicinal agents thus devolves in part on the preparation of suitable organo-substituted malonic acid esters.
Illustrative examples of other well-known members of the barbiturate family of hypnotics and sedatives derived from organo-substituted diesters of malonic acid are as follows:
5-Ethyl-5-phenylbarbiturate, (Luminal.RTM., phenobarbital), can be prepared by the reaction of ethyl phenyl malonate with urea in the presence of sodium ethoxide.
5-Ethyl-5-(1-methylbutyl)barbiturate, (Nembutal.RTM., pentobarbital), can be prepared by the reaction of ethyl-1-methylbutyl malonate in the above reaction system.
5-Allyl-5-(1-methylbutyl)barbiturate, (Seconal.RTM., secobarbital), can be prepared by the reaction of allyl-1-methylbutyl malonate in the same reaction system. See U.S. Patent 1,954,429.
5-Ethyl-5-(1-methylbutyl)-2-thiobarbiturate, (Pentothal.RTM., thiopental), can be prepared condensing ethyl-1-methylbutyl malonate with thiourea in the presence of strong base. This compound is a useful anesthetic agent. See U.S. Pat. No. 2,876,225.
5-Allyl-5-(2-cyclohexen-1-yl)-2-thiobarbituric acid, (Intranarcon.RTM., thialbarbital), can be prepared by condensation of phenyl propenyl malonate with thiourea. The sodium salt is a useful anesthetic agent. See U.S. Pat. No. 2,153,730.
Alkylation of diethyl malonate with a propargyl halide, followed by alkylation with allyl bromide yields the following organo-substituted diester of malonic acid: ##STR2## The above diester is a suitable intermediate for the production of 5-allyl-1-methyl-5-(1-methyl-2-pentynyl) barbituric acid, (Brevital.RTM., methohexital), which is a useful anesthetic agent as the sodium salt. See U.S. Pat. No. 2,872,448.
The malonic ester required for the synthesis of the hypnotic and sedative agent, 5-allyl-5-(2-cyclopenten-1-yl) barbituric acid, (Cyclopal.RTM.), can be obtained by appropriate alkylation of diethyl allylmalonate ##STR3## with 1,2-dibromocyclopentane and excess base. See U.S. Pat. No. 1,869,666.
The carbamate sedative, carbamic ester of 5-butyl-5-(2-hydroxyethyl)barbituric acid (Nogexan.RTM., carbubarbital), can be prepared from the intermediate compound diethyl butylmalonate ##STR4## See French Patent No. M1059(1962); British Patent No. 940,533.
The diesters of malonic acid also can be converted to the corresponding glycols which are intermediates for the production of compounds that have found extensive use as drugs to relieve mild anxiety. For example, reduction of malonic ester with lithium aluminum hydride gives the corresponding glycol. Reaction of the glycol with phosgene produces an intermediate which on treatment with ammonia gives the tranquilizer, 2-methyl-2-propyl-1,3-propanediol dicarbamate, (Equanil.RTM., Miltown.RTM., meprobamate), as follows: ##STR5## See U.S. Pat. No. 2,724,720.
A similar sequence using another malonic ester, ##STR6## as the starting material, yields the hypnotic and tranquilizer, 2-methyl-2-(1-methylpropyl)-1,3-propanediol dicarbamate, (Butatensin.RTM., Carbuten.RTM., mebutamate). See U.S. Pat. No. 2,878,280.
The present invention is directed to a novel method of making terminal diesters of malonic acid of the foregoing general type which can be used as starting materials and intermediates for the production of hypnotics, sedatives, tranquilizers and anesthetics by methods similar to the above illustrative methods.